The present disclosure relates to the measurement of isometric and isotonic contraction of blood vessels and luminal organs. More particularly, the disclosure of the present application relates to devices, systems and methods for isometric and isotonic contraction of blood vessels and the determination of isometric and isotonic activity of luminal organs using an isovolumic myograph.
Vascular smooth muscle coils (VSMCs) modulate the tone of a blood vessel in response to neural, humoral or local hemodynamic stimuli. The VSMCs are important for auto-regulation and largely determine the spatial and temporal distribution of blood flow in an organ. Thus, conditions that affect the proper function of VSMCs cause a variety of medical problems.
Many diseases, including hypertension, diabetes, heart failure and atherogenesis, show signs of impaired arterial vasoactivity. Hypertension, for example, is identified in relation to changes in the myogenic tone of the resistance arteries. The vasoactivity may be attenuated due to physiological (normal growth, exercise, pregnancy, etc.) or pathological remodeling (hypertension, hypertrophy, heart failure, etc.). The pressure-induced myogenic response (or tone) is initiated as a consequence of pressure-dependent modification of vascular smooth muscle wall tension and subsequent activation of mechanosensitive ion channels. Steady-state myogenic tone accounts for a substantial portion of the peripheral resistance and is an important determinant of arterial blood pressure. Although vasoconstriction and vasodilation are intrinsic properties of VSMC, they are often modulated by endothelium-derived vasoactive factors.
Because of the importance of maintaining proper vasoactivity in VSMC, various drugs are tested for their effects on such vasoactivity. Two of the tools used in such tests to identify vasoactivity in blood vessels include the wire and pressure myographs. A Medline search with keyword “wire myograph” or “pressure myograph” reveals 140 and 207 publications, respectively, from 1990 to the present having at least some reference to these conventional tools for testing vasoactivity. In pharmacology, these methods are used to understand the vasoreactivity and the dose-response relation of various agonists and antagonists.
Although the wire myograph method is used often for pharmacological experiments, it has a number of drawbacks, one being that it is far from physiological. The mechanical deformation of the ring is non-physiological and the cutting of the vessel produces some injury to the vessel which has a direct impact on the response of the vessel to the testing. In addition, the excision of rings and attachment to hooks cause injury and lead to a non-physiological geometry and loading. Furthermore, the reference length for the vessel ring is unknown and comparison between various vessels at various conditions is difficult to standardize.
The pressure myograph was developed to address some of the limitations of the wire myograph. In the pressure myograph, the vessel geometry and loading are typically more physiological. The pressure myograph method involves changes in pressure while recording the change in diameter under passive and active conditions. The method is substantially isobaric because the pressure is maintained constant during contraction. Since the radius changes during the test, which can change the wall stress (based on Laplace's equation), this method of mechanical testing is neither isometric nor isotonic, which in turn affects interpretation of the results. Unlike the high sensitivity of wire myograph that records tension, the pressure myograph records the diameter changes under isobaric conditions and hence is limited to small vessels that have substantial vasoactivity. Hence, there is currently no unified myograph that applies to small as well as large vessels under identical geometry, loading and testing protocols.
Vascular endothelial dysfunction is widely considered to be a consequence, a biomarker and a mediator of the adverse effects of cardiovascular risk factors. Endothelial dysfunction precedes the development of morphological atherosclerotic changes and can also contribute to lesion development and later clinical complications. Endothelial dysfunction has also been shown to be a predictor of adverse outcomes in patients with coronary artery disease. Ongoing efforts to identify and develop new drugs for the treatment of atherosclerosis depend on robust evaluation of vascular lesion pathology in preclinical models, a time consuming approach associated with significant variability of the data.
The stomach is largely dependent upon extrinsic nervous inputs arising from the central nervous system. These inputs regulate the smooth muscles and coordinate the digestive function of stomach by parasympathetic and sympathetic pathways. The excitatory neurotransmitters by efferent vagus fibers (mainly acetylcholine and tachykinins) cause rhythmic contractions of gastric smooth muscles. The gastric smooth muscles exhibit the tone on which there is superimposition of rhythmic contractions driven by cycles of membrane depolarization and repolarization.
In addition, it has been known for nearly three decades that the gastric mechanoreceptors which respond to gastric muscular distension and contraction are implicated in post-prandial satiety, in sensing the effectiveness of a contraction to expel contents, and in a variety of reflexes. Electrophysiological studies in different species have shown that mechanosensitive afferent fibers located in the antrum muscle wall respond to changes in smooth muscle transmural and local tension with an increased firing rate. Gastric distension is correlated with a firing of vagal mechanosensitive afferent fibers, which play an important role in satiety.
The physical forces that act on the intestinal wall during the intestine contraction propels chyme. The intestinal tract is abundantly innervated with mechanosensors in response to the physical forces in intestinal wall when a meal transits through the gut. The excitation of extrinsic sensory afferents provides clear evidence on the intestinal mechanosensory endings in response to distension, responding to mechanical stimulation arising during distension and contraction. The level of mesenteric afferent firing is a proportional increase when the intraintestinal pressure increases. Brain-gut interactions are recognized as major players the in physiological and pathpophysiological regulation of the intestinal tract, as the intestinal tract possesses an intrinsic nervous plexus (pacemaker) that allows the intestine to have a considerable degree of independent control from central nervous system.
Intestinal motility is one of the objectives of central nervous system and local nervous regulation. Intestinal motility disorders exist in a pathological state, such as intestinal obstruction or ileus. Laparotomy and manipulation also interfere with intestinal movements. The most widely accepted explanation of postoperative ileus was based on the idea that manipulation inhibited motor function through some sort of neurologic reflex response. Experimental studies have identified central neural influences that mediate ileus of the gastrointestinal tract. Three main mechanisms are involved in its causation, namely neurogenic, inflammatory and pharmacological mechanisms. In the acute postoperative phase, mainly spinal and supraspinal adrenergic and non-adrenergic pathways are activated. However, although the mechanical sensory and afferent excitation in response to mechanical stimulation have been extensively studied, the alteration of intestinal motility in response to mechanical stimulation is poorly understood since the response of the motility experiences a cycle of the intestinal sensor to afferent nerve to central nervous system to efferent nerve finally back to intestinal smooth muscle.
Thus, although both of the above conventional methods are widely in use, a need exists in the art for an alternative to the conventional techniques for testing vasoactivity in blood vessels such that the need addresses the setbacks and limitations of the conventional techniques, while at the same time, is easy to use and interpret and provides a more accurate measurement of vasoactivity. In addition, a need also exists in the art for various devices, systems, and methods to determine isotonic and isometric of non-vascular luminal organs, such as the stomach and the intestines.